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Abstract

Arthroscopic meniscal treatment is the most common procedure performed in the orthopedic practice. Current management of meniscal pathology relies on different therapeutic options, ranging from selective meniscectomy, suturing, and to meniscal replacement by using either allografts or scaffolds. The progresses made in the field of regenerative medicine and biomaterials allowed to develop several meniscal substitutes, some of those currently used in the clinical practice. Before reaching the clinical application, these devices necessarily undergo accurate testing in the animal model: the aim of the present manuscript is to systematically review the scientific evidence derived by animal model results for the use of meniscal scaffolds, in order to understand the current state of research in this particular field and to identify the trends at preclinical level that may influence in the near future the clinical practice.

Thirty-four papers were included in the present analysis. In 12 cases the meniscal scaffolds were used with cells to further stimulate tissue regeneration. With the exception of some negative reports regarding dacron-based scaffolds, the majority of the trials highlighted that biomaterials and bio-engineered scaffolds are safe and could play a beneficial role in stimulating meniscal healing and in chondral protection. With regard to the benefits of cell augmentation, the evidence is limited to a small number of studies and no conclusive evidence is available. However, preclinical evidence seems to suggest that cells could enhance tissue regeneration with respect to the use of biomaterials alone, and further research should confirm the translational potential of cell-based approach.

INTRODUCTION

The first arthrotomic procedure on meniscus was performed by Robert Annandale at the end of the 19th century [1], and from that moment onwards meniscal surgery has become common in the everyday orthopaedic practice. For the most part of the 20th century the main procedure on meniscus was removal of the damaged tissue, which was further diffused by the advent of arthroscopy that contributed to minimize surgical trauma and accelerate knee function recovery. It took almost one hundred years to achieve, in 1984, the first meniscal allograft transplantation, which opened the era of biological replacement [2]. Nowadays, the current management of meniscal pathology is focused on preserving the meniscal tissue as much as possible, in order to prevent the early onset of osteoarthritis (OA) in the affected compartment [3, 4]. To this purpose, beyond meniscal allografts, which are indicated in case of previous total or sub-total meniscectomy, new biomaterials have been brought into clinical practice: these scaffolds are used to replace partial meniscal defects [5], since it has been demonstrated that even a partial meniscectomy is able to alter joint biomechanics, determining an over-load in the affected compartment [3]. In this perspective, the possibility of using biomaterials able to stimulate meniscal tissue regeneration represents an innovative approach that could prevent patients from receiving more invasive surgery at young age. In fact, despite the costs linked to the use of such biomaterials, the possibility of preventing the onset of an early degenerative articular pathology is surely attractive and not only from the patient perspective, since it could also determine, on a large scale, a reduction in the expenses afforded by Health Systems to manage a chronic and invalidating condition such OA. To this purpose, it is useful to underline that more than 500,000 arthroscopies are performed every year to address meniscal pathology [5] and, therefore, it is easy to understand that the clinical implication and societal impact of novel regenerative procedures could be huge.

At present times there are two meniscal substitutes used in clinical practice: the first one is a collagen based meniscal implant, whereas the second and more recent one is made of polyurethane and polycaprolactone. Both of them have been investigated in a number of clinical trials, that revealed the safety of these implants and also their capability of improving knee functional status up to the possibility of resuming sport practice [6-8]. Imaging and, in some cases, arthroscopic evaluation confirmed the potential of these bio-engineered devices to stimulate meniscal tissue regeneration, although not in a complete manner. In some trials, these meniscal scaffolds have also been applied, together with cartilage treatments and osteotomies, to perform a biological knee reconstruction as salvage procedure in patients affected by unicompartmental OA and otherwise doomed to metal resurfacing [9]. Currently, this particular area of research, which is particularly based on biomaterials and bio-engineering, is moving forward to develop new products that could promote a better tissue regeneration and determine superior and longer-lasting clinical outcome.

The aim of the present manuscript is to systematically review the scientific evidence for the use of meniscal scaffolds derived by animal model results, in order to understand the current state of research in this particular field, underlining in particular the materials that have been tested, the outcomes in terms of meniscal regeneration, and the role played by cellular augmentation. Identifying the trends emerged at preclinical level that may lead to better understand the evolution in this particular area of research and shed light on the solutions that might be introduced in clinical practice in the near future.

MATERIALS AND METHODS

A systematic review of the literature was performed on the application of meniscal scaffolds / meniscal bio-engineered substitutes in the animal model. The search was made on the PubMed database on March 1st, 2015 using the following formula: (meniscal scaffold or meniscal substitute or meniscal replacement or meniscal biomaterial) AND (animal or horse or pig or goat or sheep or bovine or ovine or rat or rabbit or monkey or dog or primate). The screening process and analysis were performed separately by 2 independent researchers.

First, the articles were screened by title and abstract. The following inclusion criteria for relevant articles were used during the initial screening of titles and abstracts: reports of any level of evidence, written in the English language, with no time limitation, on the application of meniscal scaffold/meniscal bio-engineered substitutes in the animal model. Exclusion criteria were: articles written in other languages, human trials, and reviews. In the second step, the full texts of the selected articles were screened, with further exclusions according to the previously described criteria. Reference lists from the selected papers were also screened. Relevant data were then extracted and collected in a single database with consensus of the two observers to be analyzed for the purposes of the present manuscript. At the end of the process, 34 papers fulfilled the selection criteria and have been described in the following paragraphs (Fig. 1).

Fig. (1).

Flow Diagram describing the papers selection process.

Fig. (2).

Numbers of papers published per time interval from 1980 up to today. (Note that the data for 2011-2015 period are still provisional).

RESULTS

A total of 34 papers fulfilled the inclusion criteria and were analyzed. The first paper was published in 1983 and, over the years, it was possible to observe an increasing interest by scientists in this particular area of musculoskeletal regenerative medicine (Fig. 2).

With regard to the animal models used, 1 paper dealt with the goat model, 1 paper with pig, whereas 8 papers with sheep, 13 with the rabbit, 10 with the dog, and 1 with both dog and pig model respectively. Furthermore, in 12 papers, cells (from different sources) were tested together with the meniscal scaffolds. Results will be described according to the animal model used and, when applicable, the particular cellular augmentation used will be also discussed.

A summary of all the studies included in the present review has been reported in Table 1.

Table 1.

Synopsis of animal trials dealing with the application of meniscal scaffolds.

Defects filled completely with the new meniscal tissue only for the cells transfected with hIGF-1 + scaffold group. Larger fibro-chondrocytes number and higher percentage of cartilage-like tissue for transfected cells group.

Neo-meniscus tissue ingrowth
Tissue integration between the original meniscus and the implant
Cartilage degeneration occurred in the joints.

Kon E,
Tissue Eng Part A
2008
[15]

Sheep

Total medial meniscectomy

Hyaluronic acid and polycaprolactone composite

Autologous chondrocytes

Two fixation techniques: with or without trans-tibial horn fixation

Cell-seeded scaffolds
Cell-free scaffolds
Empty controls

6 months

Superior fibrocartilage formation in the cell-seeded group.
Better implant macroscopic appearance and integrity when the scaffold was fixed without trans-tibial horn suture.

Kon E,
Tissue Eng Part A
2012
[16]

Sheep

Total medial meniscectomy

Hyaluronic acid and polycaprolactone composite

Autologous chondrocytes

-

Cell-seeded scaffolds
Cell-free scaffolds
Empty controls

12 months

Cell-seeded scaffold had better tissue regeneration capacity with more fibrocartilaginous tissue.
Chondroprotective effect of the scaffold, although no difference was documented between cell-seeded and cell-free groups.

Promising results for hydrogel meniscal implants seen at early time points follow-up.
However, at 12 months follow-up significant cartilage degeneration and implant failure for hydrogel meniscal group compared to allograft transplantation.

No significant differences in terms of cartilage degeneration between scaffold and control group.

Gruchenberg K, Knee Surg Sports Traumatol Arthrosc
2014
[20]

Sheep

Partial medial meniscectomy

Silk fibroin scaffold

-

-

Scaffold group
Empty defect

6 months

No inflammation occurred in scaffold implanted group.
No significant differences in cartilage degeneration between the scaffold and sham group.
Loss of the implant in 3 of 9 cases in scaffold group
Mechanical properties of the scaffold similar to the native meniscal tissue.

Sommerlath K, Am J Sports Med. 1992
[21]

Rabbit

Total meniscectomy and Incised meniscus

Dacron prosthesis with polyurethane coating

-

-

Prosthesis group
Incised meniscus group
Resected meniscus group

3 months

Cartilage degeneration presented in 70% of the prosthesis implanted group, compared to only 25% in the group with meniscal incision
No positive results regarding healing tissue for prosthesis group compared to incised meniscus or sham operated group

Sommerlath K, Clin Orthop Relat Res. 1993
[22]

Rabbit

Incised meniscus and total meniscectomy

Dacron meniscus prosthesis

-

-

Prosthesis group
Incised meniscus
Resected meniscus

3 months

Rare ingrowth but stable fixation of the prosthesis
Prostheses implanted group showed the same incidence and severity of OA as the resected meniscus group

Messner K Biomaterials. 1993
[23]

Rabbit

Total meniscectomy

Dacron and Teflon prosthesis

-

-

Dacron implant group
Teflon implant group
Resected meniscus group
Non operated group

3 months

Cartilage degeneration observed for both implants
No positive results for implants (same results as the resected meniscus group)

Testa Pezzin AP, Artif Organs. 2003
[24]

Rabbit

Total medial meniscectomy

Poly(p-dioxanone)/poly(L-lactic acid), PPD/PLLA

-

-

Scaffold group
Empty defect

3, 6, 12,
and 14 weeks

Better tissue regeneration in scaffold implanted group compared to control group (empty defect)

In all groups except cell-free implants, improvement in healing of the defect.
Non pre-cultured MSCs in the scaffold stimulated the regeneration of meniscus-like tissue.
Pre-cultured MCSs showed only partially integration with the native meniscus.

Regeneration of fibrocartilage with maintained original shape and structure of neomeniscus.
Biochemical and mechanical analysis differed from native meniscus.

Esposito AR, Biores Open Access. 2013
[32]

Rabbit

Total medial meniscectomy

poly(L-co-D,L-lactic acid)/poly(capro-lactone-triol) scaffold

Rabbits, fibro-chondrocytes

Fibrochondrocytes preseeded on the scaffold expanded in vitro for 21 days

Scaffold + cells
Scaffold without cells
Empty defect

12 and 24 weeks

Good integration of the implanted scaffold into native tissue.
No rejection, infection and inflammation observed.
Better results in generating of fibro-cartilaginous tissue towards cell-seeded scaffold compare to scaffolds without cells.

Only group with hCDMP-2 expressing myoblasts produced regenerating tissue, with positive staining for coll I and II and S-100 protein.
Faster healing within red-red vs white-white zone.

Goat Model

The only available trial on the goat model [10] focused on a calcium alginate-based meniscal scaffold augmented with bone marrow mesenchymal stem cells (MSCs). Interestingly, in one of the treatment groups tested by the authors, the bone marrow cells, before being added to the scaffold, were transfected to over-express the insulin-like Growth-Factor 1 (hIGF-1): results were in favor of this genetically manipulated group, since 16 weeks after implantation a complete filling of the meniscal defect and a better histological outcome in cartilage and extra-cellular matrix healing was obtained with respect to the non-transfected BMSCs group, which on the other hand performed better than the scaffold alone group.

Pig Model

The pig model was used to evaluate a vycril mesh scaffold [11], which was tested alone and in association with autologous and allogeneic chondrocytes. Also in this trial a beneficial effect of cellular augmentation was noted: in fact, the best histological outcomes and the larger meniscal healing (12 weeks after implantation) were achieved in the autologous chondrocyte group, followed by the allogeneic chondrocyte group and then by the scaffold alone group.

The pig model was also used to explore the potential of a collagen-based scaffold in a study focusing also on findings obtained in the dog model, thus results will be reported in the following relative paragraph [12].

Sheep Model

Eight papers investigated the results of meniscal scaffolds in the sheep model.

Chiari et al. [14] used a hyaluronic acid/polycaprolactone meniscal substitute to treat 8 sheep, where the scaffold was used to fill either partial or complete meniscectomies. The implants tested were mechanically stable and showed excellent tissue ingrowth to the capsule. Tissue integration was also observed between the original meniscus and the implant. The histological investigation revealed tissue formation, cellular infiltration and vascularization. After these promising findings, further studies were conducted with the same scaffold. In particular Kon et al. [15] tested the scaffold, in 24 sheep, with or without autologous chondrocyte seeding. In the same trial, also two different fixation techniques were compared: in one case the scaffold was just sutured to the capsule and meniscal ligament, whereas in the other case a trans-tibial fixation of both horns was added. At 6 months’ evaluation, excellent capsular ingrowth was present in all the implants tested; in terms of fibrocartilage formation the addition of autologous chondrocyte proved to be beneficial, whereas better implant appearance and integrity were documented without trans-tibial fixation [15]. In a later study with evaluation performed up to 12 months [16], it was confirmed that seeding the scaffold with autologous chondrocytes increases tissue regeneration capacity, providing a better fibrocartilaginous tissue formation with respect to cell-free scaffold. Authors also revealed that osteoarthritic changes over time were significantly less in the cell-seeded group than in the meniscectomy controls, even though results were not significantly different between cell-seeded and cell-free scaffold [16], thus suggesting that the chondroprotective effect is not directly influenced by cellular addition.

Kelly et al. [17] employed, instead, a hydrogel meniscal implant which was compared to three different treatment groups: meniscal allograft transplantation, empty defect, and sham surgery. Overall results were positive for the hydrogel implant at early follow-up (2 and 4 months) but, at the last evaluation at 12 months, significant cartilage degeneration was observed in the compartment and all the implants presented signs of mechanical failures consisting in complete radial tears located in the posterior third of the implant. The outcome of this hydrogel scaffold was significantly lower than that of the meniscal allograft. Maher et al. [18] reported the results after implanting a porous polyurethane scaffold in a partial lateral meniscectomy model: the evaluations performed 12 months post-op. revealed tissue ingrowth within the scaffold without cartilage damage. However, comparison regarding the status of tibial plateau cartilage did not reveal any significant difference between scaffold implanted and control (untreated) group due to the unexpected tissue self-regeneration occurring in the sheep partial meniscectomy model.

The results of a kevlar-reinforced polycarbonate-urethane scaffold were reported by Zur et al. [19], who found that this kind of biomaterial could provide a chondroprotective effect and reduce cartilage degeneration over time: the authors compared the operated knee with the contralateral healthy one at 3 and 6 months’ follow-up and showed no significant difference in cartilage status between treated and control limbs.

Finally, Gruchemberg et al. [20] tested a silk fibroin scaffold and documented the absence of inflammatory response after implantation, a beneficial effect in preventing cartilage degeneration, and also mechanical features of the regenerated tissue comparable to the native meniscus, even if in three cases mobilization of the scaffold occurred.

Rabbit Model

The first study on the rabbit model dates back to 1992 [21], when a Dacron meniscus prosthesis with polyurethane coating was used. Results of this trial were fairly negative, since poor tissue healing was observed, with low scaffold integration, and the meniscal substitute did not prevent cartilage degeneration with respect to the meniscectomized control group. The same negative outcomes were later reported using two different variants of the aforementioned Dacron meniscal prosthesis: in one case the scaffold was made of Dacron alone (without any coating) [22] whereas in the other one there was the addition of Teflon [23]. In neither cases the scaffolds proved to be beneficial in terms of tissue healing and chondroprotection, thus sentencing the ineffectiveness of this particular construct for meniscal regeneration.

In more recent times new biomaterials have been tested with more encouraging results. Testa Pezzin et al. [24] developed a Poly(p-dioxanone)/poly(L-lactic) acid scaffold which provided good mechanical stability after implantation and showed to stimulate tissue regeneration. Similarly, the group led by Kobayashy has published 3 papers where they tested a polyvinyl alcohol-hydrogel (PVA-H) artificial meniscus which exhibited enough mechanical resistance without dislocation or breakages and showed a chondroprotective effect in the lateral compartment where it was implanted. The authors evaluated the outcome of this meniscal scaffold implantation up to 2 years, documenting lower OA progression in the scaffold group with respect to empty controls [25-27].

Angele et al. tested a hyaluronan/gelatin composite scaffold with and without pre-cultured bone marrow-derived MSCs: at 12 weeks of follow-up the best results were obtained in the cell-augmented group, where meniscus-like fibrocartilage was documented and also a greater cross-sectional width of the scaffolds with respect to cell free implants, which produced mainly fibrous repair tissue [28].

In 2010 Zellner et al. [29] evaluated the use of cell augmentation to a hyaluronan/collagen meniscal scaffold tested in the rabbit model. In this trial 5 different treatment groups were compared: empty defect, scaffold + bone marrow concentrate (BMC), scaffold + platelet-rich plasma (PRP), scaffold + pre-cultured chondrogenic MSCs, scaffold + non precultured MSCs. Furthermore, the scaffold alone was used as a control in a meniscal defect created in the contra-lateral knee of all rabbits. At 12 weeks the authors documented that PRP and BMC did not improve tissue healing with respect to the scaffold alone. Histological results after using the scaffold + BMC or PRP were modest, revealing just fibrous healing in the implanted area. When looking at the scaffold + pre-cultured MSCs, a fibrocartilage-like repair was achieved with a partial integration within the native tissue. The best results were instead obtained by the scaffold + non pre-cultured MSCs, where the integration was complete and the histological aspect more similar to the native tissue [29]. The same authors, in a later similar study [30], confirmed these results, thus proving that MSCs play a crucial role in promoting a superior meniscal regeneration, at least when used together with the particular hyaluronan/collagen scaffold tested in this experimental setting [30].

A poly-glycolic acid based scaffold with the addition of expanded allogeneic meniscal cells has been used by Kang et al. as a replacement after medial meniscectomy [31]. The study, despite not having any cell-free control group, demonstrated that regenerated neomenisci were similar to normal meniscal cartilage in both gross and histological appearance. Esposito et al. tested a porous poly(L-co-D,L-lactic acid)/poly(caprolactone-triol) scaffold with and without the addition of fibrochondrocytes [32], which were pre-seeded onto the scaffold and expanded in vitro for 21 days. A good integration of the implants was observed, without signs of foreign body reaction, and better results in tissue regeneration were documented for the cell-seeded scaffold.

The most recent study on the rabbit model was published by Oda et al. [33], who tested a type I collagen scaffold with or without augmentation by infra-patellar fat pad, which is a source of MSCs. Eight week after the procedure the rabbits were sacrificed and the best meniscal regeneration (evaluated through the Ishida Score) was documented in the fat pad group, which also revealed a superior expression of type I and type II collagen at immuno-histochemical essays. Further in vivo analysis proved that the addition of infra-patellar fat pad was able to reduce the secretion of metalloproteinases and other interleukins that could impair tissue regeneration.

Dog Model

The first attempt to replace meniscal tissue was performed in 1983 by Toyonaga et al. who implanted a Teflon scaffold [34] and published the first study showing the feasibility and the potential of this novel regenerative approach. Almost a decade later, in 1992 Stone et al. [12] used a collagen based scaffold revealing promising results in terms of meniscal fibrocartilage regrowth in the dog model, although the same biomaterial proved to be less effective in the pig model tested by the same authors. More recently, a study authored by Hansen et al. [35] investigated the potential of a collagen-based scaffold: despite a documented well integration of the scaffolds, the authors reported a significant occurrence of inflammatory response after implantation, thus suggesting the necessity for further improvements of this construct.

In the following years an increasing interest emerged toward another biomaterial for tissue regeneration: polyurethane. Several studies have been published on this specific material: the first reports have been authored by the group of Klompmaker [36, 37], who documented the biocompatibility of this scaffold together with its capability of stimulating the formation of new meniscal fibrocartilage with good mechanical properties. DeGroot et al. [38] obtained good results using an aliphatic polyurethane network-organized scaffold and further studies by the same authors proved that regenerative properties of polyurethane could be improved by a chemical augmentation, using a copolymer of L-lactide and r-caprolactone aliphatic polyurethane [39]. This novel formulation allowed for a better adherence to the native tissue and was responsible for a superior tissue regeneration. Further developments were proposed and tested by Tienen et al. who realized a scaffold made of porous polyester urethanes based on l-lactide/e-caprolactone [40-42]. This meniscal substitute achieved interesting results in terms of histological and biomechanical parameters [40, 41] and, when compared to an estane-based scaffold [42], it provided slightly superior results, thus leading to its application in the clinical practice with good results as demonstrated by some human trials [7, 8]. The most recent study on the dog was published by Zhu et al. [43] who performed a complex experiment, whose principal aim was to investigate the role of hCMP-2 (Human Cartilage-derived Morphogenetic Protein 2) in meniscal repair. To this purpose, canine myoblasts were transfected with lentiviruses carrying the hCMP-2 gene. These myoblasts were then loaded onto a PLA/PGA scaffolds and the whole construct placed onto the meniscal defect site. Authors found that purified canine myoblasts expressing the hCDMP-2 gene were able to promote meniscal fibrocartilage healing: the tissue in the red-red zone was regenerated more rapidly than that in the white-white zone. Furthermore, the results obtained with this particular implant were superior to those achieved by using canine myoblasts or recombinant hCMD-2 alone.

DISCUSSION

The implantation of biomaterials to stimulate the replacement of injured meniscal tissue represents a fascinating option for clinicians, since even partial damage or removal of the meniscus have been demonstrated to alter the joint biomechanics, leading to the early onset of OA [3]. The use of meniscal scaffolds aims at giving a structural contribute for defect repair and at stimulating the healing processes of damaged tissues, in order to provide a reparative tissue that resembles the properties of the native one [5]. Our search identified an increasing number of preclinical papers dealing with scaffold-based meniscal replacement in the animal model. Various biomaterials have been investigated at preclinical level, with the aim of finding the ideal one, in terms of biocompatibility and regenerative potential, to be translated to the clinical use. Beside some negative results and some controversial findings, the overall results of the studies analyzed confirmed the potential of this approach with promising findings in terms of tissue regeneration and in some studies even a chondro-protective effect provided by the implanted biomaterial.

The systematic analysis of the available literature underlined that most papers evaluated meniscal replacement in the animal model with cell-free scaffolds. While poor results have been obtained by preliminary attempts and despite the ineffectiveness of some biomaterials, progresses made by biomaterials research in the last years have yielded to the development of a new generation of scaffolds able to stimulate the intrinsic tissue regeneration ability [44]. These cell-free scaffolds provided good results while avoiding the risks related to cell manipulation [44] (e.g. bacterial contamination and phenotype loss,…) and the regulatory limitations which may hinder a subsequent translation in the clinical practice. In this direction, various biomaterials have been developed and tested through preclinical research, with the challenge of guiding the regeneration of a tissue resembling the specifics of the native one. In general, promising results have been shown in the preclinical setting in terms of morphology and function, even though many differences emerged with respect to the healthy tissue in terms of mechanical and biochemical analysis. Beside a few constructs showing limited biocompatibility [35] or ineffectiveness in terms of chondroprotection and tissue healing [19, 21, 22], most of the biomaterials evaluated confirmed the potential of this surgical approach for the treatment of meniscal loss, with satisfactory integration of the implant and tissue regeneration. Among them, polyurethane is the most studied, with overall promising results in terms of biocompatibility and chondroprotective effect [36-42]. After these good histological and biomechanical findings, polyurethane-based meniscal substitutes are currently applied in the clinical practice, with satisfactory results at short- to mid- term follow-up [7, 8]. However, no comparative studies have been performed to prove the superiority of one biomaterial to others, and new treatments are currently being developed aiming at further improving the results obtained by this regenerative approach to treat and restore meniscal tissue damage.

Regenerative treatments are a complex and rapidly evolving field of medical research, where an increasing number of papers shows similar good results for many different products. Moreover, beside the literature limitations which do not allow to clearly prove superiority of one procedure to the others, several not scientific factors also influence the research direction, such as economic and regulatory aspects [46]. In this scenario, cells occupy a controversial role: in fact, despite the good results suggested for cell augmentation, currently preclinical research is focusing more on the evaluation of cell-free constructs [45], and cell-free techniques are the only ones translated into the clinical practice, where no trials about cell-augmented techniques have been reported yet. The use of cell-free scaffolds allows to avoid the regulatory obstacles and the costs related to cell manipulation, and also the more complex organization needed to offer a cell-based treatment [44, 47], but some animal trials suggested that cell-augmentation might provide superior regenerative potential in terms of tissue quality. However, the combination of scaffolds and cells has not been extensively investigated and only a few comparative studies are currently available, so it is not possible to draw definitive conclusions on the real effectiveness of cell augmentation. Moreover, the real clinical benefit remains unknown, both in terms of function improvement and joint preservation, and further research is needed in this direction. The analysis of the cell sources also showed no sufficient evidence, and the available evidence doesn’t provide clear indications for the most suitable one. MSCs have been increasingly used because of their characteristics, which would suggest them as the ideal source for regenerative procedures due to their properties of self-renewal and stemness maintenance, their potential for differentiation into cells forming multiple mesodermal tissues, other than their trophic and immuno-modulatory effects [48]. On the other hand, other studies applied cultured meniscal cells, chondrocytes or fibrochondrocytes, and overall good results have been reported also when using differentiated cells. Regardless of the limits of the literature, the controversial findings, and the need for further studies, it is important to underline that among the studies reporting on cell-augmented scaffolds, in general, superior results were reported adding cells compared to scaffold alone or even to PRP augmented implants. However, these papers present with a marked heterogeneity in terms of different cell sources, dosage, scaffold materials, animal models, and defect types, thus making difficult to draw a conclusion on the real effect of cells on the scaffold-based approach. Beyond cellular augmentation, also novel bio-engineered strategies are currently under investigation in the attempt of improving tissue regeneration: a few recent studies tested the use of growth factors (such as IGF-1 and hCMP-2) through cellular transfection using viral vectors [10, 43]. The results reported seem to be quite encouraging even if the very low number of trials and the large variety of molecules that could be potentially used warrant further research in this particular field, remembering that such approaches are extremely expensive and, at least for the moment, their translational potential is limited also by ethical and regulatory issues.

Among the literature limitations, beside the heterogeneity of the biomaterials, cell sources and processing methods, and the lack of comparative studies which prevents to clearly identify which techniques are more effective, other aspects should be considered since they may influence the outcomes of the regenerative procedures evaluated in these studies. First, the choice of the experimental model is key for the success or failure of each construct, with results varying according to the type of animal evaluated, and also the type of lesion, medial or lateral, partial or complete, acute or chronic etc… may influence the results documented on the potential of the studied scaffolds.

When looking at clinical practice, it is important to remember that scaffolds are used mainly in chronic meniscal lesions rather than in acute lesions (which is instead the classical setting of animal trials): sometimes scaffolds are implanted many years after meniscectomy and the articular environment could play a key role in determining the success of meniscal regeneration. Furthermore, meniscal scaffolds in clinical practice are used to treat just partial meniscal defects, whereas in the animal model scaffolds are often used as total meniscal replacement: it is still unclear, in the human setting, if a critical size exists beyond which the mechanical stability and/or the regenerative potential of scaffolds is impaired. Moreover, the preclinical level gives important indications for the development of new treatments, but it doesn’t completely mirror the human setting. For example, collagen scaffolds that have shown controversial results in the animal model [12, 35], have been extensively used on humans with satisfactory outcomes [42], and on the other hand it is also possible that biomaterial suggesting good results in the animal model may not be as successful after reaching the clinical practice.

In conclusion, the present review underlined the potential of biomaterials’ implantation in terms of meniscus regeneration and chondral protection, but at the same time it highlighted the difficulties in understanding the most suitable scaffold and surgical approach, due to the heterogeneity of products used and preclinical models, as well as the design of the published studies. The literature analysis highlighted that biomaterial properties, such as biocompatibility, are key for the success of such regenerative procedures, which may provide beneficial effects in the treated joints, and limited but consistent evidence suggests that cell-augmentation may be beneficial for scaffold-based meniscal tissue regeneration. Nonetheless, clinical research is currently focusing on cell-free procedures, due to several reasons including scientific, economic, and regulatory aspects, and good results have been obtained in humans treated with these meniscal scaffolds. The overall preclinical evidence supports the use of scaffolds to restore meniscal tissue damage, and progresses in biomaterial properties may further improve the results obtained by the currently available scaffolds. High quality studies are needed to prove the benefit of each technique by directly comparing different strategies, increasing the knowledge on scaffold-based treatments and the best ways for exploiting the self-regenerative potential of the body. Among the most promising strategies to improve the final outcome, cell augmentation deserves particular attention. The available preclinical evidence, despite being not conclusive, suggests that cells may enhance tissue regeneration with respect to the use of biomaterials alone, which warrants further research in this direction. Exploring the best cell sources, manipulation and application modalities could contribute to a possible translation of bioengineered tissues in the clinical practice, being aware, however, that the beneficial effects of cellular augmentation reported in animal trials might be not confirmed when used in the human model.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The present manuscript was partially supported by “European Project BIOINSPIRE- Training program on new bio-inspired bone regeneration (FP7-PEOPLE-2013 ITN-607051)”.

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About the Editor

Biography of Philippe Hernigou

Dr. Philippe Hernigou, Ph.D., is currently Professor in the Department of Orthopaedic Surgery at Paris 12 Val de Marne University, Créteil, France. Dr. Hernigou is member of the International Hip Society, SICOT treasurer, member of the French Academy of Surgery, and Past-President of SOFCOT (French Orthopaedic Society). He, as an author/co-author, has been involved in the publication of more than 255 articles in various journals from around the world, having a significant number of total citations, i.e. around 5,130. He has published mainly in the subject areas of Biochemistry, Genetics and Molecular Biology.

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If you are interested in becoming our Editorial Board member, please submit the following information to info@benthamopen.net. We will respond to your inquiry shortly.

Email subject: Editorial Board Member Application

Your name

Email address

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Name of your institution

Department or Division

Website of institution

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Complete list of publications and h-index

Interested field(s)

Testimonials

"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."

. —Daniel Pesut. (Indiana University School of Nursing, USA).

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."

. —Patrice Talaga. (UCB S.A., Belgium).

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."

. —Jeffrey M. Weinberg. (St. Luke's-Roosevelt Hospital Center, USA).

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."

. —Debomoy K. Lahiri. (Indiana University School of Medicine, USA).

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."

. —Robert Looney. (Naval Postgraduate School, USA).

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."

. —Richard Reithinger. (Westat, USA).

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."

. —J. Ferwerda. (University of Oxford, UK).

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."

. —Sean L. Kitson. (Almac Sciences, Northern Ireland).

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."

. —Hubert Wolterbeek. (Delft University of Technology, The Netherlands).

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."

. —Alessandro Laviano. (Sapienza - University of Rome, Italy).

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."

. —Philippe Hernigou. (Paris University, France).

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."

. —M. Bendandi. (University Clinic of Navarre, Spain).

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."

. —Peter Chiba. (University of Vienna, Austria).

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."

. —Eduardo A. Castro. (INIFTA, Argentina).

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."

. —Kenji Hashimoto. (Chiba University, Japan).

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."

. —Daniel Shek. (Chinese University of Hong Kong, Hong Kong).

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."